Chapter 4 │ Page 143 study modulated expression levels rather than the absolute positivity of tumor cells, as indicated by the Overton analysis. (Supplementary Figure 2). Apart from MICA/B, other stress-induced proteins are also known to contribute to NK cell activation, such as ULBPs [26] and membrane-bound HSP70 [74, 75]. Investigating the e ect of NTP treatment on the expression of such stress-induced membrane proteins would further expand our understanding of how NTP can modulate the recognition of cancer cells by NK cells, and will form the subject of future work. In addition, while oxidative modifications likely play a role in later biological observation as well, it is expected that a complex network of biological mechanisms takes place over time, moving from the immediate chemical character to 24 hours post-treatment, such as protein degradation (e.g., via proteasomal pathways) and alterations in protein tra icking to and from the cell membrane [31, 32, 76]. Furthermore, oxidative stress can trigger signaling pathways that regulate the stability and localization of membrane proteins. NTP treatment can also modulate gene expression, leading to changes in the synthesis of key proteins that disrupt membrane lipid organization and impact the localization of proteins associated with lipid rafts [18, 56]. Deeper exploration of these underlying pathways can be built on the work presented here. Consequently, a detailed temporal analysis of ligand expression over a series of time points could provide valuable insights into the kinetic profile and dynamics of NTP's pleiotropic e ects. It is apparent that sensitivity to NTP and the resulting outcome varied between the studied cell lines. While Cal27 and SCC61 were derived from tongue lesions [77, 78], the SCC22B cell line, originated from a metastatic lymph node in the neck [78]. Interestingly, the expression profiles of Cal27 and SCC61 cells clustered together, whereas the SCC22B cells exhibited a markedly distinct therapeutic response, particularly for the expression of CD112 and CD73. To underline this, we repeated the analysis for CD47, an innate immune cell checkpoint which was previously studied in our lab [32], for the cell lines investigated in the present paper. Indeed, NTP
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